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Original Research Communication |
1 From the Department of Pathology and Laboratory Medicine, the University of Toronto and Mount Sinai Hospital, Toronto, Canada, and DiaSorin Inc, Stillwater, MN.
2 Supported in part by a grant from the Dairy Farmers of Canada. P-CR Chan was a recipient of a postdoctoral fellowship in Clinical Chemistry from the Ontario Ministry of Health.
3 Address reprint requests to R Vieth, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5. E-mail: rvieth{at}mtsinai.on.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: Our objective was to assess the efficacy and safety of prolonged vitamin D3 intakes of 25 and 100 µg (1000 and 4000 IU)/d. Efficacy was based on the lowest serum 25-hydroxyvitamin D [25(OH)D] concentration achieved by subjects taking vitamin D3; potential toxicity was monitored by measuring serum calcium concentrations and by calculating urinary calcium-creatinine ratios.
Design: Healthy men and women (n = 61) aged 41 ± 9 y (
± SD) were randomly assigned to receive either 25 or 100 µg vitamin D3/d for 2–5 mo, starting between January and February. Serum 25(OH)D was measured by radioimmunoassay.
Results: Baseline serum 25(OH)D was 40.7 ± 15.4 nmol/L ( ± SD). From 3 mo on, serum 25(OH)D plateaued at 68.7 ± 16.9 nmol/L in the 25-µg/d group and at 96.4 ± 14.6 nmol/L in the 100-µg/d group. Summertime serum 25(OH)D concentrations in 25 comparable subjects not taking vitamin D3 were 46.7 ± 17.8 nmol/L. The minimum and maximum plateau serum 25(OH)D concentrations in subjects taking 25 and 100 µg vitamin D3/d were 40 and 100 nmol/L and 69 and 125 nmol/L, respectively. Serum calcium and urinary calcium excretion did not change significantly at either dosage during the study.
Conclusions: The 100-µg/d dosage of vitamin D3 effectively increased 25(OH)D to high-normal concentrations in practically all adults and serum 25(OH)D remained within the physiologic range; therefore, we consider 100 µg vitamin D3/d to be a safe intake.
Key Words: Cholecalciferol • calcidiol • vitamin D3 • hypercalciuria • toxicity • lowest observed adverse effect level • LOAEL • efficacy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Directly related to this issue is the question of how much vitamin D is needed to ensure target serum 25-hydroxyvitamin D [25(OH)D] concentrations. According to the recommended dietary allowances, persons should achieve "levels of intake of essential nutrients considered. . . to be adequate to meet the known nutritional needs of practically all healthy persons" (2, 6). Serum 25(OH)D is the appropriate index of vitamin D nutritional adequacy (1). Therefore, the nutritional need for vitamin D would be the amount of it needed to ensure for "practically all healthy persons" that serum 25(OH)D concentrations are maintained above a concentration considered adequate. Moderate vitamin D malnutrition is based on what is now well documented—an inverse relation between serum 25(OH)D and parathyroid hormone (PTH) concentrations (7–9). 25(OH)D concentrations <40–50 nmol/L are considered to be insufficient (10–12). Because the suppression of PTH is seen as beneficial for bone, many now regard serum 25(OH)D concentrations 
75–100 nmol/L as desirable. This is the concentration at which PTH approaches a minimum in its relation with 25(OH)D (7, 9, 11, 13–15).
An intake of 100 µg vitamin D3 (cholecalciferol)/d may be required to ensure desirable 25(OH)D concentrations (16). However, because such intakes exceed the LOAEL, it is not feasible to use them in studies of healthy adults, especially in long-term studies designed to evaluate health effects. Ethical review panels may be hesitant to approve the use of a dosage that exceeds the LOAEL, funding agencies may be hesitant to provide the funds needed for such study, and study subjects themselves may have or develop reservations that could lead to poor study compliance.
There are few data from which to establish vitamin D safety and toxicity limits. Some studies that might be considered relevant because they include data on serum calcium, urinary calcium, or both have major shortcomings, eg, 
6 subjects (3, 4, 17), follow-up times 3 mo (3, 18, 19), nonspecification of the form of vitamin D used (vitamin D2 or vitamin D3) (3, 4), or nonverification of the accuracy of the stated dose (3, 4). The objectives of the present study were to assess the efficacy of high vitamin D intakes, in terms of the serum 25(OH)D concentrations ensured for practically all adults, and to monitor the long-term safety of vitamin D3 intakes that exceed the LOAEL.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Subjects were randomly assigned to receive a vitamin D3 intake of either 25 or 100 µg/d; only data for subjects who consumed vitamin D3 for 1 mo are provided. The doses were assigned randomly by distributing the 2 dose formats in equal numbers through a partitioned rack from which each subject's first coded vial was taken, in sequence, without the giver's or the subject's knowledge of the dose it contained. Of the 73 subjects enrolled initially, 61 completed 1 mo of the protocol. The study began between January and February (baseline, time 0). At 0, 0.5, 1, 2, 3, 4, and 5 mo of vitamin D3 supplementation, a morning urine sample (second void of the day) was collected and one tube of blood was collected to prepare serum for biochemical testing. At the time of each blood sampling, the vials that had contained the vitamin D3 solutions were collected to monitor compliance and subjects were given fresh vials. Subjects were free to withdraw from the study at any time and their withdrawal is reflected in the number of points shown in the figures. When insufficient serum samples were available from the clinical service laboratory, 25(OH)D concentrations were not measured; the measurement of calcium was given priority. Blood was collected from 25 laboratory coworkers who did not take part in the vitamin D intake study; this group served as an end-of-study reference group.
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Assays
Serum 25(OH)D was measured by radioimmunoassay (DiaSorin, Stillwater, MN). Serum calcium and phosphate and urinary calcium, phosphate, and creatinine were measured with an Integra automatic chemistry analyzer (Roche, Basel, Switzerland). Urinary calcium excretion was assessed as a ratio of urinary calcium to creatinine concentrations (4, 21).
Statistical analyses
Safety and efficacy were assessed by using repeated-measures analysis of variance (ANOVA) followed by Dunnett's multiple (pairwise) comparison t test to determine the CI for the mean differences from baseline at each time point (release 6.12; SAS Statistical Software, Cary, NC). A two-tailed P value < 0.05 was considered significant. For regression lines plotted nonparametrically, we used the locally weighted regression and smoothing scatterplot (LOWESS) approach (22) using SPSS statistical software (versions 8 or 10; SPSS Inc, Chicago). This software was also used for paired t test comparisons with baseline values.
Criteria for safety and efficacy
The efficacy of a given dose of vitamin D3 was based on the final serum 25(OH)D concentration (not its change). A dose was considered effective if it ensured a serum 25(OH)D concentration 75 nmol/L (7, 9, 11, 13–15). A dose was considered safe if all of the following criteria were met:
2.75 mmol/L (11 mg/dL) during vitamin D supplementation, the criterion used by others to support the current LOAEL (1); 1.0 (when calcium and creatinine are measured in mmol; 0.37 when measured in mg) during vitamin D supplementation; and |
RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Serum 25(OH)D concentrations during the supplementation protocol are shown in Figure 1. With the 100-µg/d dosage, repeated-measures ANOVA and post hoc comparisons with Dunnett's test indicated that serum 25(OH)D increased significantly beginning at 2 wk until the end of the study. With the 25-µg/d dosage, repeated-measures ANOVA and post hoc comparisons with Dunnett's test indicated a significant increase from only 1 mo on. A conventional paired t test showed the expected significant increase in 25(OH)D at 2 wk (P < 0.01). At 3 mo, serum 25(OH)D concentrations peaked at 68.7 ± 16.9 nmol/L in the 25-µg/d group and at 96.4 ± 14.6 nmol/L in the 100-µg/d group and remained relatively stable at these concentrations for the remainder of the study. For each group, the final 25(OH)D concentration attained was not significantly affected by either the initial 25(OH)D concentration or by body weight (Figure 2). From 3 mo on, the minimum and maximum of the plateau serum 25(OH)D concentrations were 40 and 100 nmol/L in the 25-µg/d group and 69 and 125 nmol/L in the 100-µg/d groups. The 25-µg/d dosage was effective at ensuring 25(OH)D concentrations of 75 nmol/L in 8 of the 23 (35%) subjects. The 100-µg/d dosage was effective at ensuring 25(OH)D concentrations of 75 nmol/L in 22 of the 25 (88%) subjects.
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. In all subjects in the 25- and 100-µg/d groups, serum calcium concentrations remained within the reference range (2.2–2.6 mmol/L). There was no significant change from baseline in serum calcium at any time by repeated-measures ANOVA. CIs for the differences between serum calcium concentrations during the study and baseline values were consistently 0.10 mmol/L. The upper 97.5% confidence limits for the mean difference in serum calcium results are illustrated in Figure 3 and they show with statistical confidence (P < 0.05) that the values were consistently <2.45 mmol/L. Similarly, there was no significant change from baseline in urinary calcium-creatinine excretion ratios at any time point by repeated-measures ANOVA. The upper confidence limits for the differences between baseline urinary calcium-creatinine excretion ratios and those during supplementation were consistently <0.70 (Figure 3). There were more urinary calcium-creatinine excretion ratios >1.0 in the 100-µg/d group (in one subject, 2 of 6 values were >1.0 during treatment) than in the 25-µg/d group. The relative number of occurrences of hypercalciuria across the entire follow-up period was not significantly different between the 2 dosage groups on the basis of chi-square tests. Similarly, the relative number of treated subjects with hypercalciuria was not significantly different from the number of untreated subjects (baseline) with hypercalciuria. More subjects than were used here will be required to show whether the higher dose does in fact increase the occurrence of hypercalciuria. The paired t test, which was used to compare baseline values with those during treatment, is less appropriate than is ANOVA with this study design, but is more sensitive for detecting changes from baseline. Like the ANOVA, paired t tests showed no significant changes in serum calcium concentrations or urinary calcium-creatinine ratios at any time point during the 5-mo vitamin D intake period.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The results of the present study differ slightly from those of earlier studies in that we did not detect an effect of treatment on urinary calcium excretion. Our urine samples were collected from nonfasting subjects at the second void of the morning (collected before 1000). Collection times in other studies were not specified and the subject populations may have differed from ours. Tjellesen et al (18) used the same dosage we did and showed small but significant increases in urinary calcium-creatinine excretion ratios. Arthur et al (17) reported a 50% increase in urinary calcium-creatinine ratios in 6 women who took 350 µg vitamin D2/d for 16 mo (17). Adams and Lee (4) reported 4 cases of vitamin D intoxication on the basis of only increased fasting urinary calcium-creatinine ratios.
For people with serum calcium concentrations in the reference range, the implications of high-normal urinary calcium concentrations need to be understood better before this can be regarded as an adverse response. Until there is more evidence to verify the safety of intakes of 100 µg vitamin D/d, it is simple and prudent to continue to monitor calcium in randomly collected urine samples. Although randomly collected urine samples can be affected by large calcium loads in the hours before collection (25, 26), 24-h collections are notoriously affected by improperly timed collections, missed urine voids, and daily variations in calcium intake. Calcium concentrations in randomly collected urine samples correlate well with calcium concentrations in 24-h urine samples (21, 27–30). The mean calcium-creatinine ratio in randomly collected urine samples from nonfasting groups of healthy subjects is 
0.40 (0.14 when measured in mg) (29, 31, 32). A 24-h urinary calcium excretion >10 mmol/d (400 mg/d) is considered to indicate hypercalciuria (33). Graphs of regression data for the relation between random urinary calcium-creatinine ratios versus 24-h calcium excretion (21, 28) indicate that at a 24-h calcium excretion of 10 mmol/d, the nonfasting random calcium-creatinine ratio is 1.0 (0.37 when measured in mg). In our study there were more urinary calcium-creatinine ratios >1.0 in the 100-µg/d group than in the 25-µg/d group, but the difference was not significant.
In the absence of hypercalcemia, urinary calcium excretion is a minor contributor to renal stone disease. Stronger risk factors for calcium oxalate stones include low urine volume, hyperoxaluria, and hypocitraturia. Urinary calcium is useful for classifying normocalcemic patients who already have stone disease (34), but it cannot discriminate adults who form calcium oxalate stones from those who do not form kidney stones (33, 35). Furthermore, it is highly controversial whether isolated high-normal calcium excretion contributes adversely to either stone disease or bone health (33, 35–37). Because it is impossible to prove by statistical analysis that an agent has no harmful effect, we can only conclude that an intake of 100 µg vitamin D3/d is safe because there was no convincing evidence of harm.
Throughout the history of vitamin D supplementation in North America, high-dose preparations of the vitamin D2 form have generally been used. Vitamin D3 is common in lower-dose regimens, but in some parts of the world vitamin D2 is the only form licensed for use. In terms of rickets prevention, research from the 1930s was inconclusive at detecting a difference in efficacy between the 2 forms of vitamin D; therefore, pharmacopoeias continue to regard vitamin D2 as being equivalent to vitamin D3, even though the latter form is more effective at raising serum 25(OH)D concentrations (20). What seems to have been forgotten is that the literature of half a century ago established that, at high doses, there was a greater risk of toxicity with what was called "the purely artificial" compound, vitamin D2 (38–40). One explanation for the difference in toxicity was the poorer stability and greater impurity of vitamin D2 than of vitamin D3 preparations (38). There are newer reasons why vitamin D2 has a greater potential for harm. First, vitamin D binding protein has a weaker affinity for the vitamin D2 metabolites than for 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 (41–43). This means that the proportions of free 25-hydroxyvitamin D2 and 1,25-dihydroxyvitamin D2 are higher and more biologically available. Second, unique biologically active metabolites are produced from vitamin D2 in humans and there are no analogous metabolites derived from vitamin D3 (44). There is no doubt that vitamin D2 is a synthetic analogue of vitamin D, with different characteristics. It is an anachronism to regard vitamin D2 as a vitamin. Future research into the toxicology of this vitamin needs to focus on vitamin D3 as being something distinct from vitamin D2, for which almost all our current toxicity data relate to.
The working definition of the recommended dietary allowance has been to ensure "levels of intake of essential nutrients considered, in the judgment of the Food and Nutrition Board on the basis of available scientific knowledge, to be adequate to meet the known nutritional needs of practically all healthy persons" (2, 6). For vitamin D, the relevant question could be, what 25(OH)D concentration is desirable and how much vitamin D is needed to ensure that most adults attain this intake (45)? We did not measure PTH in this study, so we cannot address the question of what the desirable vitamin D intake is. However, the present results do provide insights into the lowest 25(OH)D concentrations that can be reasonably ensured in adults consuming 25 and 100 µg vitamin D3/d. The 25-µg/d intake offered reasonable assurance that serum 25(OH)D concentrations in adults would be >40 nmol/L, but did not ensure that most subjects would attain serum 25(OH)D concentrations considered desirable (>75 nmol/L). The 100-µg/d intake offered reasonable assurance that 25(OH)D concentrations in adults would be >69 nmol/L (Figures 1 and 2
), close to the lower end of the desirable concentration.
If the serum 25(OH)D concentration is the appropriate measure of vitamin D nutritional adequacy (1), then more of the present type of specific data are needed to define the amounts of vitamin D required to ensure that for "practically all healthy persons" serum 25(OH)D concentrations are maintained above an amount considered adequate. There are subgroups who require 25 µg vitamin D/d to maintain acceptable 25(OH)D concentrations. Gloth et al (46) reported that in older patients with 25(OH)D concentrations <25 nmol/L, vitamin D intakes ranged as high as 29 µg/d. Patients with cystic fibrosis require >20 µg vitamin D/d to maintain 25(OH)D concentrations >40 nmol/L (47). Despite the greater number of subjects and the longer follow-up in the present study than in previous comparable studies (3, 18, 19), consumption of vitamin D3 at intakes 100 µg/d causes no harm and effectively raises 25(OH)D to high-normal concentrations in practically all adults.
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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